The results of most recent studies suggest that systemic sclerosis (SSc) is a composite disease of major histocompatibility complex (MHC)-associated autoantibody responses, which have specific clinical correlates. Both the anticentromere and anti-topoisomerase I (anti-topo I) antibody responses have been linked to HLA-DQB1 alleles, although recent data suggest that certain HLA-DRB1 alleles are important for the anti-topo I response and that HLA-DPB1 alleles also may have a role. Antibodies to the nucleolar specificity PM-Scl have consistently been linked to the HLA-DRB1*0301, DQA1*0501, and DQB1*0201 haplotypes. Antibodies against fibrillarin, another nucleolar specificity, have been linked to certain HLA-DQB1*06 alleles. With the establishment of animal models of SSc, recent attention has been drawn to other genes that may be involved in the pathogenesis of this disease. To date, however, none have been found in humans, although comprehensive studies of this type are lacking. One particularly attractive area for study is the fibrillin loci on chromosome 15, syntenic to the region on mouse chromosome 2 to which the tsk gene has been mapped. Other locations include the interleukin-1 alpha and interleukin-beta genes (or their promoters) or oncogenes. These areas should provide potentially fruitful areas of investigation in the near future.